This invention relates to surfactants which as amphiphitic molecules have a variety of applications, in particular in the preparation of liposomes, dispersions, and emulsions such as fluorocarbon emulsions.
The achievement of an intravenously injectable oxygen-delivering system has become a major objective in biomedical research. Such a system is destined to serve as a temporary substitute for blood, but also, more generally, whenever in vivo administration of oxygen is required, as for example in cases of myocardial infarction or stroke, during cardiovascular surgery, for the preservation of isolated tissues and organs, as an adjuvant to cancer radio- and chemo- therapy and in perioperative hemodilution. Fluorocarbons presently appear to be the most promising oxygen vectors for this purpose. Fluorocarbons also have significant utility as contrast enhancement agents, such as for diagnosis by X-ray, magnetic resonance or ultrasound radiography.
The intravenous injection of neat fluorocarbons is, however, precluded by their insolubility in an aqueous medium. It is therefore necessary to prepare them in the form of emulsions, which implies the use of one or more surfactants. Although albumin has been used as a surfactant, the primary synthetic surfactants used in fluorocarbon emulsions today are polyoxyethylene polyoxypropylene block co-polymers of PLURONIC F-68 type, and natural surfactants such as egg-yolk lecithins.
Lecithins, however, have their drawbacks and limitations; they are sensitive, oxidizable materials; reliable sources of consistent quality are few; they are not particularly fluorophilic; and they leave little room for manipulating the emulsions' characteristics in order to adjust them to specific therapeutic applications.
Further mastery of the art of fluorocarbon emulsion technology is desirable, especially to allow the optimal adaptation of the emulsions characteristics to each individual therapeutic application and to extend their spectrum of application. A further, ideal, objective would be the ability to modulate the biological response they trigger in the organism.
Likewise it is desirable to gain further mastery in the art of liposome technology, especially to allow the modulation of the characteristics and properties of lipid membranes and liposomes and to extend their spectrum of applications, especially for drug and contrast agent delivery.
The present invention provides various fluorine-substituted lecithin analogues and derivatives, which are useful as surfactants in fluorocarbon emulsions and in lipid membranes and in liposome manufacturing.
Certain fluorine-containing surfactants are known. For example, DE-A-2160783 discloses certain fluorocarbon phosphoric acid derivatives having a chlorine atom substituted on the carbon atom .beta.- to the phosphate group.
Fujita et al. (JP-A-60181093, Chem. Pharm. Bull., 35:647 (1987) disclose certain fluorocarbon phosphoric acid derivatives based on glycerol in which a single fluorine-containing (R.sub.F) moiety is present and the secondary alcohol function is either free (OH) or acetylated (OCOCH.sub.3). DD-A222595 discloses some fluorinated glycerophosphocholine derivatives bun these contain only a 2,2,2-trifluorethyl group.
The article by Gu et al [Chemical Abstract 110:154749c (1989); HUAXUE XUEBAO or Acta Chimica Sinica, 49:913 (1988)], discloses phosphatidylcholine derivatives having two F-alkyl chains, but these contain a chlorine atom at their extremity.
Kunitake et al (Memoirs of the Faculty of Engineering, Kyushu University 46 221 (1986)) disclose fluorocarbon phosphoric acid derivatives which contain an amide linkage, as a result of being a glutamic acid diester.
DE-A-2656429 discloses certain fluorocarbon phosphorous (not phosphoric) acid derivatives including the presence of a CH.dbd.CF double bond.
Various publications also disclose one or two fluorocarbon moieties substituted onto a phosphoric acid moiety; in the case of the mono-substituted compounds both remaining groups of the phosphoric acid are independently hydroxy, alkoxy, alkylthio or alkylamino.
DE-A-3609491, DE-A-3609492 and JP-A-84204197 disclose certain dibasic fluorocarbon-substituted phosphoric acid derivatives.
JP-A-8623590 and JP-A-86123591 (Fuji) disclose certain fluorocarbon-substituted phosphoric acid derivatives having no methylene groups.
Mahmood et al (Inorg. Chem. 25 4081 (1986)) discloses molecules having central bifunctional fluorinated chains with two phosphate groups, one on each end of the chain.
Various sulphonamides containing fluorocarbon moieties and a phosphoric acid residue are known.
U.S. Pat. No. 3976698 and U.S. Pat. No. 3948887 (Pennwalt) disclose certain sulphur-containing fluorocarbon-substituted phosphoric acid derivatives.
None of the above documents discloses the use of the surfactants disclosed in fluorocarbon emulsions. Further, none of the prior documents discloses compounds within the scope of the present invention.